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2015
Regioselective C–H bond amination byaminoiodanesAbhishek A. KantakUniversity of Rhode Island
Louis MarchettiUniversity of Rhode Island
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Citation/Publisher AttributionKantak, A. A., Marchetti, L., & DeBoef, B. (2015). Regioselective C–H bond amination by aminoiodanes. Chemical Communications,51(17), 3574-3577. doi: 10.1039/C4CC10246KAvailable at: http://dx.doi.org/10.1039/C4CC10246K
AuthorsAbhishek A. Kantak, Louis Marchetti, and Brenton DeBoef
This article is available at DigitalCommons@URI: https://digitalcommons.uri.edu/chm_facpubs/145
Regioselective C–H Bond Amination by Aminoiodanes
Abhishek A. Kantaka, Louis Marchettia, and Brenton DeBoefa
Brenton DeBoef: [email protected] of Chemistry, University of Rhode Island, 51 Lower College Rd., Kingston, RI 02881, USA
Abstract
A new approach for the direct amination of 2-phenylpyridine derivatives using a diphthalimide-
iodane and copper triflate has been developed. A series of different 2-phenylpyridine derivatives
were aminated with yields up to 88%. Mechanistic investigations indicate that the reaction
proceeds via a copper-mediated single electron transfer.
Over the past two decades advances in transition metal catalyzed C–H functionalization
have provided efficient strategies for the construction of C–C and C–heteroatom bonds.1
During this time an extensive amount of effort has been deovted to the development of novel
methodologies for the construction of C–N bonds, as they are ubiquitous in pharmaceuticals
and other high value molecules. However, synthetic routes for the direct amination of the C–
H bonds of arenes are relatively rare.2 Recent examples involve the addition of nitrene
intermediates into allylic and benzylic C–H bonds,3 though methods involving radical
intermediates have also been investigated.4,5 Most of the metal-mediated directed
aminations involve late transition metal catalysts, such as palladium or ruthenium,6 though
recently, efforts to discover highly efficient, economical, and environmentally benign
methods for C–N bond formation have led to the development of copper-mediated C–H
aminations.7,8 Notably, Yu reported a C–N bond formation process using stoichiometric
copper acetate,2b and Nicholas reported a copper-catalyzed C–N bond formation process;
however, this method required harsh conditions.9a Likewise, Li reported the copper-
catalyzed dual C–H/N–H cross-coupling of 2-phenylpyridine with acetanilide.9b
Recently, we and both Chang and Antonchick simultaneously developed an I(III)-mediated
intermolecular oxidative C–N bond formation processes for synthesizing anilines by a
formal tandem C-H/N-H activation. Though these reactions provided high yields of
amination products, the radical mechanism produced mixtures of regiomeric products for
mono-subsituted arene substrates such as toluene (Scheme 1).2d,2e,10 Subsequently, Hartwig
reported a related palladium-catalyzed amination reaction that enhanced the regioselectivity,
though both meta and para aminated products were observed for mono-substituted
substrates.11 To remedy the regioselectivity issues associated with our metal-free protocol,
Correspondence to: Brenton DeBoef, [email protected].†Electronic Supplementary Information (ESI) available: experimental details and characterization of novel compounds See DOI: 10.1039/c000000x/
HHS Public AccessAuthor manuscriptChem Commun (Camb). Author manuscript; available in PMC 2016 February 28.
Published in final edited form as:Chem Commun (Camb). 2015 February 28; 51(17): 3574–3577. doi:10.1039/c4cc10246k.
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we proposed to develop an I(III)-mediated reaction that achieved regioselectivity via a
metal-mediated C–H activation with a substrate containing a Lewis base directing group.2d
During the course of our previous investigations, we also became interested in the synthesis
of new iodane and iodonium reagents containing I–N bonds that could be used as C–H
aminating agents. Recently, Muniz reported several novel hypervalent iodine(III) reagents
for metal-free intermolecular allylic amination and diamination of alkenes.12 Furthermore,
diaryliodonium salts had been used by the Sanford group to arylate C–H bonds in the
presence of catalytic palladium13 and by the Gaunt group to arylate C–H bonds in the
presence of catalytic copper.14 Consequently, we synthesized phenyl(diphthalimido)- λ3-
iodane (3) by ligand exchange from iodobenzenebis(trifluoroacetate), PIFA, using a
relatively simple ligand exchange reaction.15 We also successfully synthesized a saccharin-
derived iodane (4) and the phthalimide-iodonium salt (5) by modifying a route for
synthesizing diaryliodonium salts from in situ-generated iodosobenzene (Scheme 2).16
The new iodanes and the iodonium salt were subjected to a variety of reaction conditions
mediated by palladium or copper with 2-arylpyridine substrates. We hypothesized that the
I(III) species would react as an electrophilic amine, and that regioselective metalation of the
ortho Caryl–H would create a nucleophilic carbon. Though this initial hypothesis proved to
be incorrect, we discovered a novel method to selectively aminate 2-phenylpyridines using
iodanes such as 3, the results of which are presented herein.
As a control, we began by heating a solution of phthalimide, 2-phenylpyridine (6), and
iodobenzene diacetate (PIDA) in acetonitrile using microwave irradiation and determined
that PIDA was not able to directly aminate the pyridine derivative. As a result, the addition
of catalytic palladium, along with PIDA or PIFA, was also explored. While modest
amination was observed, palladium catalysis did not facilitate amination with acceptable
yields. Interestingly, the use of the iodane oxidant (3) provided the desired amination
product (7), while the iodonium oxidant (5) exclusively provided the arylated product (8).
Consequently, we concluded that the iodane structure apparently favoured C–N bond
formation, while the iodonium favoured C–C bond formation. The reason for this trend is
not readily apparent and will be the subject of future studies.
As a result, we elected to screen copper catalysts and discovered that copper(II) triflate
showed higher amounts of amination products when compared to the previously successful
experiment with palladium acetate, albeit at a higher catalyst loading (Table 1, entry 2).
The reactions were sluggish, even at 145 °C, so as a compromise, we elected to increase the
catalyst loading to 1 equiv. Such a consideration is only possible when dealing with
affordable and non-toxic metals such as copper, as opposed to precious metals, like
palladium.
Further optimization indicated that Cu(OTf)2 was the preferred copper salt and that
dichlorethane (DCE) was the preferred solvent (See supporting information). Cu(OAc)2 and
CuCl2 provided low yeilds of 10 along with acetylated and chlorinated by-products (Table 1,
entries 8 and 9). When optimizing the stoichiometry necessary for the iodane, an interesting
pattern was observed. Since the I(III) species acted as both the nitrogen source and the
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oxidant in reactions containing substoichiometric Cu(OTf)2, 3 had to be used in excess.
However, when reactions containig stoichiometric Cu(OTf)2, were run with 1 equiv of 3,
lower yields were also observed (entry 6), so the excess iodane reagent was determiend to be
optimal.
Optimized conditions required heating the iodane (3), the 2-arylpyridine substrate (9) and 1
equiv of copper triflate in dichloroethane at 80 °C for 48 h (entry 5). Amination was
exclusively observed at the ortho position, relative to the pyridine substituent to yield 10,
and no arylated products (e.g. 8) were observed. The presence of the iodane was crucial for
the reactivity of the system, as reactions employing both stoichiometric copper and
phtalimide produced only trace amouts of 10 (entry 7). It is also should be noted that freshly
prepared iodane (3) exhibited higher yields than batches that had been stored under air at
room temperature.
A variety of 2-phenylpyridine substrates could be aminated using the optimal reaction
conditions (Table 2). First, substrates containing different phenyl-substituted groups were
screened. 4–Tolylpyridine (10) showed a comparable yield to unsubstituted 2-
phenylpyridine (7); however, substrates having additional electron density, such as the 4-
methoxy derivative (12), showed a drop in yield. Additionally, it appears that the central
dihedral angle of of the biaryl substrate may also play a part in determining the substrate’s
reactivity, as benzo[h]quinoline, a substrate commonly employed in C–H activation
reactions, produced only trace yields of the aminated product (13). Substitution on the
pyridine ring of the substrate did not appear to dramatically affect the reaction. Fluorination
of the pyridine directing group did not dramatically alter the yield of the amination, but
fluorination of the phenyl ring caused the yield to drop (compare 7, 14 and 18).
Additionally, the amination reaction proceeded with the saccharin iodane (4), to yield the
expected aminated product (20). To elucidate the reaction mechanism, competition studies
were conducted using an equimolar mixture of two different pyridine substrates in the lead
reaction. In each case, amination of the more electron rich arene was favored over the
electron poor arene.
The kinetic isotope effect was also studied using an intramolecular competition between a
C–H bond and C–D bond in 2-phenylpyridine. The observed KIE of 1.15 indicates that C-H
bond cleavage was not involved in the rate-determining step. This rules out the possibility of
a metal-mediated C–H activation step via oxidative addition, σ-bond metathesis, or
concerted metalation-deprotonation, where significant isotope effects are usually observed.
Additionally, the substrate scope (Table 2), and the competition studies (Table 3) indicate
that the reaction favors electron rich arenes, which could be easily oxidized. Thus, we
propose a pathway mediated by a radical cation (23) to explain the data (Scheme 4).2b
First, copper triflate reacts with the iodane (3) to generate a copper-phthalimide species (21)
and the iodonium (5). We have detected the formation of 5 via mass spectrometry of crude
reaction mixtures, and we have independently synthesized and characterized it (Scheme 2).
Thus, we propose that 21 reacts with 2-phenylpyridine (6) to generate a complex having
Cu(II) coordinated to the pyridine substrate (22). A single electron transfer (SET) from the
aryl ring to the coordinated Cu(II) generates the radical cation intermediate (23). Homolytic
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cleavage of the Cu–N bond and subsequent intramolecular anion transfer from the Cu(I)
intermediate generates the ortho-aminated product (7). Competition studies show that the
reaction is favored when an electron donating group is present on the aryl ring, and the SET
from an aryl ring containing an electron-donating group should be faster than that from an
aryl ring containing an electron withdrawing group. We propose that SET is the rate-limiting
step in this reaction.
In conclusion, we have developed a novel, useful and economical process for the direct
amination of 2-phenylpyridine derivatives. This process requires cheap and commercially
available copper triflate and works for a variety of different 2-phenylpyridine derivatives.
Additionally, the process also works with a bis-saccharin iodane. Future endeavors aim to
synthesize additional novel iodanes that contain I–N bonds in order to further develop this
and other amination processes.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
This work was supported by the National Science Foundation (CAREER 0847222), and the National Institutes of Health (NIGMS, 1R15GM097708-01).
Notes and references
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Scheme 1. Amination of arenes in the absence of a transition metal catalyst
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Scheme 2. Synthesis of imide-substituted iodanes and an iodonium salt
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Scheme 3. Palladium catalyzed reactions of 3 and 5
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Scheme 4. Proposed mechanism for the regioselectiveamination
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Table 1
Discovery of the regioselective amination of 2-arylpyridine derivativesa
Entry Cu reagent (loading) Iodane (3) loading Yield (%)[b]
1 None 2.5 equiv 0
2 Cu(OTf)2 (25 mol%) 2.5 equiv 63[c]
3 Cu(OTf)2 (25 mol%) 1 equiv 47[c]
4 Cu(OTf)2 (0.5 equiv) 2.5 equiv 71[c]
5 Cu(OTf)2 (1.0 equiv) 2.5 equiv 88[c]
6 Cu(OTf)2 (1.0 equiv) 1 equiv 80[c]
7 Cu(OTf)2 (1.0 equiv) None[d] 2
8 Cu(OAc)2 (1.0 equiv) 2.5 equiv 12
9 CuCl2 (1.0 equiv) 2.5 equiv 5
[a]General reaction conditions: 9 (0.146 mmol), 3 (0.365 mmol), catalyst (0.25–1 equiv) and DCE (4 mL), heated in avial in an oil bath for 48 h.
[b]GC yield.
[c]Yield of isolated products after column chromatography.
[d]This reaction contained 1 equiv phthalimide.
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Table 2
Substrate Scopea
aIsolated yields following flash chromatography.
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Table 3
Competition Reactionsa
Entry R1 (Py-Ar1-H) R2 (Py-Ar2-H) Χ Py-Ar1-NPhth Χ Py-Ar2-NPhth
1 H Me 42 58
2 H F 92 8
3 Me F 94 6
aMole fractions determined by GC
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